1. Field of the Invention
The present invention generally relates to the fields of organic synthesis, carbohydrate chemistry and peptidomimetics.
2. Description of Related Art
In vivo, peptides are subjected to numerous cellular processes such as proteolytic cleavage, degradation, (de)glycosylation and the like, all of which impact the half-life of the peptide. These are important considerations when the peptide is acting as a pharmaceutical compound, as a longer half-life means longer effectiveness and fewer administrations.
For example, amino acids containing basic side chains (e.g., lysine, ornithine and arginine) occur frequently in antimicrobial peptides (AMPs). Although the mode of action of AMPs is not fully understood, most AMPs appear to manifest their biological action by enhancing the permeability of lipid membranes of pathogenic cells. This typically involves initial electrostatic interactions between the positively charged basic side chains to the negatively charged lipid membrane of pathogens, followed by adoption of an amphipathic α-helical or β-sheet structure (Hancock, 1998; Hancock and Scott, 2000). Although more potent antibiotics exist, the ability to kill target cells rapidly, unusually broad activity spectra against some of the more serious antibiotic resistant pathogens and relative difficulty with which mutants develop resistance in vitro make AMPs attractive targets for drug development (Hancock, 1998; Hancock and Scott, 2000). However, in vivo studies of many cationic peptide antibiotics have been disappointing most likely due to the fact that many AMPs exhibit poor bioavailability, susceptibility to proteolytic cleavage and low antimicrobial activity (Latham, 1999).
Other amino acids have been manipulated in an effort to minimize in vivo degradation processes, such as proline. Proline plays an important role in the formation of secondary structures in peptides and proteins because it induces a reversal in backbone conformation resulting in the formation of reverse turns and disruption of helices and sheets in proteins. Besides the occurrence of proline in β-turns, proline-rich sequences also exist as extended helices (Kakinoki et al, 2005) (polyproline-I and polyproline-II) and antimicrobial peptides (Reddy et al., 2004). In addition, proline occurs in many peptide-based lead compounds, such as AMPs and peptides with cancer-selective toxicity. Hydroxylated proline residues occur in nature in the form of collagenous peptides, virotoxin cyclic heptapeptides (Buku et al., 1980) and other peptides (Nakajima and Volcani, 1969; Taylor et al., 1994) and the role of hydroxylated proline residues on the conformational stability of the collagen triple helix has been extensively investigated (Vitagliano et al., 2001). Over the years a plethora of proline analogs such as Cβ-, Cγ- and Cδ-substituted prolines (Beausoleil and Lubell, 1996; Delaney and Madison, 1982; Samanen et al., 1990; Quancard et al., 2004), azaprolines (Che and Marshall, 2004), pseudoprolines (Tam and Miao, 1999), silaproline (Cavelier et al., 2002), proline-amino acid chimera (Sharm and Lubell, 1996) and fused bicyclic proline (Jeannotte and Lubell, 2004) analogues have been developed to study the structural and biological properties of proline surrogates in peptides (Cluzeau and Lubell, 2005; Blankley et al., 1987; Dumy et al., 1997; Li and Moeller, 1996). However, in vivo studies of many proline containing peptides exhibit poor bioavailability susceptibility to proteolytic cleavage.